Over the past several years, we have examined the molecular and cellular mechanisms of axon sprouting and reactive synaptogenesis. It is postulated that reactive synaptogenesis is part of an ongoing plasticity mechanism which can rebuild brain circuitry after minor cell loss such as occurs in aging and some degenerative diseases. We have studied these processes in the rodent brain, particularly following entorhinal lesions, and in the human Alzheimer's disease (AD) brain where entorhinal neurons also degenerate. Indeed, we and others find that many of the changes identified in the rodent brain also occur in the AD brain. Unique to AD, however, is the formation of senile plaques. It appears that one of the events occurring in the AD brain is the diversion of neuritic growth into senile plaques and the initiation of a cycle of sprouting, degeneration, and regeneration. This appears to be an example of dysfunctional plasticity which may place stress on neurons, contribute to synaptic dysfunction, and foster plaque formation. We hypothesize that one of the key molecular factors that has a central role in dysfunctional plasticity is beta-amyloid (Abeta). Abeta may enter cascades and disrupt them. That is, Abeta may organize the normal sequence of events following injury and induce a sequence of pathological cellular and molecular cascades. After injury to the healthy hippocampus, microglia and astrocytes regulate a sequence of cellular and molecular events that participate in and coordinate the removal of degenerating debris and initiate axon sprouting. Many of the same reactions occur in AD, however, Abeta reorganizes the normal cellular and molecular events, makes them largely irreversible, and engages a molecular cycle of localized growth and degeneration. The morphological hallmark of this mechanism is the senile plaque. As the plaque develops from an initial Abeta deposit, glial cells become involved and neurites, both sprouting and degenerating, become associated with the plaque. A central focus of this research will be to examine the role of glial cells, select trophic factors, heparan sulfate, and Abeta in relationship to brain plasticity and plaque formation. Recent preliminary data suggest that Abeta may have a profound influence on astrocyte and microglia function. Specifically, we will examine the action of Abeta as an "activating" factor for astrocytes, define the structure/activity relationship of the interaction and the ability of Abeta to initiate production of other molecules which, in turn, may further plaque progression, e.g., production of FGF-2, Apolipoprotein E and even amyloid precursor protein (APP) itself. We will examine the nature of signal transduction processes drawing initially from clues derived from studies on neurons. Studies in vitro will be paralleled by analyses in vivo and in postmortem control and AD tissues. Specifically, by using double and triple labeling methods and immunohistochemistry, we will continue to define the stages and mechanisms of plaque formation. We will determine whether astrocytes precede or follow Abeta condensation as indicated by thioflavine staining. We will also define whether astrocytes precede neuritic involvement. The stage at which astrocytes begin to participate will be compared to that for microglia. Finally, we will continue to pursue collaborations with other investigators in this program. In particular, we will examine neuronal responses of Abeta on APP processing in collaboration with Drs. Van Nostrand and Glabe, thrombin/Abeta actions on neurons with Dr. Cunningham, and aspects of glial regulation with Drs, Gall and Cunningham.